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Series GSE136634 Query DataSets for GSE136634
Status Public on Apr 07, 2020
Title Clinical and biological implications of target occupancy in chronic lymphocytic leukemia treated with acalabrutinib
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in chronic lymphocytic leukemia (CLL). Target occupancy has been measured as a pharmacodynamic parameter in clinical studies of covalent BTK inhibitors. However, the kinetics of BTK turnover, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remains undefined. This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily or 200 mg once daily in 48 patients with relapsed/refractory or high-risk treatment naïve CLL. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% CI 78.9%, 99.9%) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI 70.0%, 97.8%) with twice daily dosing and an ORR of 79.2% (95% CI 57.9%, 92.9%) and an estimated PFS rate at 24 months of 87.2% (95% CI 57.2%, 96.7%) with once daily dosing. BTK resynthesis was faster in CLL than in healthy volunteers. Twice daily dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared to once daily dosing. Additional follow-up is required to address the impact of dosing schedule and BTK occupancy on long-term clinical outcomes.
Overall design RNA sequencing of CD19+ peripheral blood mononuclear cells and lymph node core biopsies before and during treatment with acalabrutinib
ACP = acalabrutinib
BID = twice daily
QD = once daily
D3/4/5 = day 3/4/5 of treatment
C1/6 = after cycle 1/6 of treatment
Contributor(s) Sun C, Kendall E, Pirooznia M, Wiestner A
Citation(s) 32202637
Submission date Aug 29, 2019
Last update date Jun 02, 2021
Contact name Mehdi Pirooznia
Phone 410-340-6052
Organization name National Institutes of Health
Street address 12 SOUTH DR
City Bethesda
State/province MD
ZIP/Postal code 20892
Country USA
Platforms (1)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
Samples (124)
GSM4053613 ACP01-BID-Pre
GSM4053614 ACP01-BID-D4
GSM4053615 ACP02-QD-Pre
BioProject PRJNA562903
SRA SRP219651

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE136634_Gene_count_matrix.txt.gz 6.5 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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